Abstract

Abstract A variety of different techniques have been used for the assessment of the blood pressure response to changes in salt and water balance in humans. These have generally been found to be reproducible and to yield congruent results. This review surveys the characteristics of subjects identified as salt sensitive and salt resistant by different investigators from demographic and physiological perspectives.

The relationship between dietary salt intake and the development of hypertension has been the subject of passionate, continuing debate for decades.12345678910 Despite abundant epidemiological, experimental, and interventional observations demonstrating a link between salt and blood pressure, skepticism remains. In some instances, this skepticism is based on the observation that not all individuals have demonstrable changes in blood pressure after ingestion of increased or decreased amounts of sodium chloride. Other researchers point to the meager effects on blood pressure after modification of sodium intake in groups of normotensive or hypertensive subjects. Still others accept an effect of reduced salt intake on blood pressure but consider it to be of modest degree and one that is difficult to maintain given the hedonistic preference for salt of many individuals in acculturated societies. This view has been extrapolated therapeutically to hypertensive individuals by offering pharmacological therapy, frequently with natriuretic agents, to accomplish blood pressure reduction without requiring the individuals to alter their dietary habits. This review does not intend to participate in these emotional and subjective points of view but rather to examine the evidence supporting heterogeneity of human blood pressure responses to alterations in sodium and extracellular fluid balance and the mechanisms that have been invoked for them.

Suffice it to say that epidemiological observations, despite their flaws, have established a generally curvilinear relationship between dietary salt intake, whether inferred from urinary sodium excretion or dietary history, and the occurrence of hypertension and its consequences, primarily stroke.11 In societies in which habitual salt intake is less than 50 to 100 mmol/d, hypertension and its complications are rare, whereas the frequency of both increase at higher levels of salt intake. Thus, the inability to demonstrate a strong relationship between sodium intake and blood pressure within a population in which habitual sodium intake is relatively generous (>120 mmol/d) does not deny such a relationship if individual differences in susceptibility or temporal factors may influence the blood pressure response to such intake. In other words, individuals who are susceptible to salt-induced alterations in blood pressure may be balanced by those in whom such an effect is negligible. Alternatively, if a long period of exposure to increased sodium intake is required for blood pressure manifestations to be apparent, the age of the population studied may influence the observations. For these reasons, information from more dramatic manipulations of sodium balance may provide greater insight into the relationship between salt and blood pressure.

Salt Sensitivity: Methods and Definition

The concept of heterogeneity of blood pressure responsiveness to alterations in dietary sodium intake was first suggested by studies in 19 hypertensive subjects who were observed after a “normal” (109 mmol/d), “low” (9 mmol/d), and then “high” (249 mmol/d) sodium intake.12 Blood pressure fell significantly (P<.05) in the entire population with dietary salt restriction and increased significantly (P<.05) back to baseline levels after the high salt phase. When individual blood pressure responses to the low and high salt periods alone were compared, all but 1 subject demonstrated an increase. The investigators then arbitrarily separated the population into two groups, identifying one as salt sensitive (n=9), those who demonstrated at least a 10% increase in mean arterial pressure when the low and high salt pressures were compared, and the other as non–salt sensitive (n=10), those having smaller increases in blood pressure with salt loading. These observations in hypertensive patients were then extended to the normotensive population by studies in individuals who were subjected to an incremental range of sodium intake from 10 to 1500 mmol/d13 or to a 3-month period of modest (<80 mmol/d) dietary salt restriction.14 In the first study of 16 normotensive young men, blood pressure was measured after a 7-day period of 10 mmol/d sodium and then successive 3-day periods of 300, 600 or 800, and 1200 or 1500 mmol/d. Blood pressure rose significantly (P<.001) from the lowest to the highest salt intake. However, as shown in the Figure⇓, the individual responses were variable and ranged from an increase of 1.5% to 34%. No subject demonstrated a decrease in blood pressure when the values following the lowest and highest sodium levels were compared.

Percentage change in mean arterial pressure in normotensive subjects receiving incremental increases in sodium. Blood pressure at the end of 7 days of low (10 mmol/d) salt intake was taken as baseline. All subjects demonstrated an increase in blood pressure with salt loading. Data adapted from Luft et al.13

In a longer study of modest salt restriction conducted in 82 normotensive subjects,141516 a significant (P<.01) decrease in blood pressure was observed (mean, 4.0±1.1/3.2±1.0 mm Hg). However, when individual blood pressure responses were examined, decreases in systolic and diastolic pressures of 20 mm Hg were seen as well as increases of systolic pressure exceeding 10 mm Hg and of diastolic, 6 mm Hg. It is not likely that these changes were due to random variations of blood pressure because they were based on blood pressures measured in the home environment with a random-zero sphygmomanometer and use of the average of the last two of three consecutive readings obtained on five separate occasions in the baseline period and five separate occasions during the dietary restriction period; values were then analyzed statistically by repeated-measures ANOVA.

We arbitrarily defined salt sensitivity in these normotensive subjects as a decrease in mean arterial pressure of at least 3 mm Hg following the period of dietary salt restriction and defined salt resistance as an increase of the same magnitude.16 Those demonstrating changes between these levels were considered indeterminate with respect to classification. Using these criteria, we found that 42% of these normotensive subjects were salt sensitive and 18% were salt resistant, with the remainder having responses that we considered indeterminate.

A variety of investigators have reported results of studies in normotensive and hypertensive subjects using alterations in dietary sodium content and classifying the subsequent blood pressure responses.15161718192021222324252627282930 The majority of these observations have been made in hypertensive subjects, but some have included normotensive subjects as well. The criteria for the definition of salt “sensitivity,” “nonsensitivity,” “resistance,” and “counterregulation” of blood pressure have varied markedly. Most of these studies have been performed in relatively small numbers of subjects, usually fewer than 50, thus making it difficult to control or identify potentially confounding demographic variables. Only a few studies252930 have reported the reproducibility of the blood pressure responses to the dietary methods used, providing fuel for skeptical critics.

Several studies conducted by our group over the past 25 years have provided a great deal of information on this issue. As part of a carefully controlled evaluation of hypertensive patients for secondary forms of hypertension and as an aid to physiological subclassification of the patients for further study, we developed a rapid procedure for inducing extracellular sodium and volume expansion and contraction and applied this technique to 378 normotensive volunteers, who provided normative data, and 198 essential hypertensive patients.1631 The protocol was conducted on a metabolic unit and began with the intravenous administration of 2 L normal (0.9%) saline over 4 hours in the morning.32 Blood pressure was measured at the completion of the infusion at noon. On the following day, sodium and volume depletion was induced by a 10 mmol sodium diet and three doses of oral furosemide (40 mg each). Blood pressure was again measured on the following morning. The responses were heterogeneous and formed a gaussian distribution in both normotensive and hypertensive groups.16 The hypertensive patients, as a group, were significantly (P<.001) more salt sensitive than the normotensive individuals. We arbitrarily classified salt sensitivity as a decrease in mean arterial pressure greater than or equal to 10 mm Hg and salt resistance as a decrease less than or equal to 5 mm Hg when the two blood pressure measurements were compared. The salt-resistant group included those individuals demonstrating an actual increase in blood pressure after salt and water depletion. Those with a decrease in blood pressure between 6 and 9 mm Hg were considered indeterminate. We found that 26% of the normotensive subjects were salt sensitive and 58% were salt resistant; in the hypertensive group, 51% were sensitive and 33% were resistant. More recently, we have studied subjects on two occasions over a period of 1 year and found the blood pressure responses to be highly reproducible (P<.02).33 In addition, we have compared the response to the rapid sodium and volume expansion and contraction protocol with a dietary protocol with sodium intake greater than or equal to 200 mmol/d for 5 days followed by 7 days of sodium intake less than or equal to 15 mmol/d and observed significant (P<.02) congruence of the blood pressure responses to the different maneuvers in the same individual.34 A similar significant congruence of blood pressure response has been reported in normotensive subjects studied during dietary and intravenous salt-loading protocols by other investigators.35

Demographic Factors Influencing Salt Sensitivity

Despite differences in the methods used in the evaluation of salt sensitivity and the variability in how this phenomenon has been defined by different investigators, several consistent demographic factors have emerged from these diverse studies when sufficient numbers of subjects have been recruited to enable them to be identified. Blacks have been consistently shown to have a greater frequency of salt sensitivity than whites. We observed that 73% of black hypertensive patients were salt sensitive compared with 56% of a white hypertensive group; but in the normotensive population, the frequency of salt sensitivity among blacks (36%) was similar to that seen among whites (29%).16 Similar observations of a greater frequency of salt sensitivity among blacks have been reported in other studies.3036

Age has also been found to be related to salt sensitivity of blood pressure in the majority of studies. In the large epidemiological INTERSALT study,37 the relationship between sodium excretion and blood pressure was most notable when examined on the basis of age. Only a few studies using interventions to assess salt sensitivity have included large enough numbers and a sufficient age range of subjects to be able to identify such a relationship. Increasing salt sensitivity has been noted with increasing age in several such studies.1629333839 This relationship appears to be stronger in hypertensive than in normotensive individuals.33 Moreover, we have recently reported observations in subjects who were followed for at least 10 years after the initial classification of salt sensitivity. We found that salt-sensitive individuals had a rise in blood pressure over time that was significantly (P<.001) greater than in those who were salt resistant.33 This observation confirms the suggestion by Sullivan30 indicating that normotensive salt-sensitive subjects are more likely to become hypertensive when followed over a period of time; however, no data were provided in support of this contention. A recent report of observations in 46 essential hypertensive patients suggests that salt sensitivity of blood pressure can be observed only in individuals over the age of 45 years.40 However, reports of salt sensitivity in obese adolescents would imply that it can occur in younger subjects as well.24

An influence of sex has been suggested by some investigators41 who found salt sensitivity among female hypertensive patients but not in males when changed from a diet containing 15 g/d salt to one containing 3 g/d. Other investigators have not confirmed this effect of sex on salt sensitivity.1639 In view of the age-related effect cited by many investigators, such a separate sex effect may be difficult to discern. Another possible explanation is that since women are typically lighter in weight than men and since all of the studies examining salt sensitivity have administered a uniform amount of sodium to all subjects in each phase of the study, women may have received a greater salt load on a body weight basis than did men, thus making it more likely that a response would be observed in women.

If the “dose” of sodium per unit body weight was a major determinant of salt sensitivity, then one would expect the phenomenon to be less frequent in obese subjects than in subjects of normal or lean body weight. This has not been found to be the case, and in fact, salt sensitivity has been reported to be positively correlated with body weight in at least one study.29 However, a more recent report by the same investigators indicated that this correlation was not seen.40 Most large studies of salt sensitivity have failed to identify a relationship with body weight.16 A more consistent finding has been the alteration in salt sensitivity of blood pressure after weight loss in obese subjects.2442

Another intriguing aspect of blood pressure response to sodium appears to be the time of day that the sodium is consumed. In a study of seven normotensive Japanese women evaluated with 24-hour ambulatory blood pressure monitoring while ingesting 12 g of salt in their diet, it was observed that the average blood pressure was higher and the circadian pattern was altered when 9 g was consumed at lunchtime and the remainder in the evening compared with 9 g in the evening and the balance at lunchtime.43 Thus, this preliminary finding suggests that the timing of sodium ingestion influences the blood pressure response.

Familial and Genetic Factors

Some researchers have suggested that a family history of hypertension is associated with salt sensitivity of blood pressure, implying that this phenomenon may be genetically mediated. One group of investigators, conducting studies in two apparently different populations, have reported contradictory findings regarding this issue.2940 There are several possible explanations for this confusion, one of which is the questionable validity of estimates of familial blood pressure status that are often based on conjecture and speculation rather than actual blood pressure measurement or documentation. In a Japanese population, a positive family history was more frequently reported among salt-sensitive subjects.44 In another study, which used the blood pressure response to 0.6 mg/d 9-α-fludrocortisone (Florinef) given for 3 weeks for the definition of salt sensitivity, the investigators found a significantly greater blood pressure response in normotensive sons of hypertensive fathers than in similar individuals who had no paternal history of hypertension.45

The possibility of a genetically mediated mechanism for the blood pressure response to alterations in sodium or water balance was suggested by our studies.46 We found that salt sensitivity was more likely to be observed in individuals with the homozygous haptoglobin 1-1 genotype than in those with the 2-2 genotype and that individuals with the heterozygotic 2-1 genotype had responses that were intermediate between the other two groups. These findings were seen in both normotensive and hypertensive populations participating in two entirely different protocols for the assessment of salt responsiveness.46 This observation was recently confirmed by studies in a Japanese population, in whom the frequency of the haptoglobin 1-1 genotype is much less common than in Americans. This study demonstrated a greater frequency of salt sensitivity among Japanese with the haptoglobin 1-2 genotype than among those who were homozygous for 2-2.47 These investigators also examined polymorphisms for angiotensin-converting enzyme and were unable to identify differences in salt sensitivity based on the three different patterns (II, ID, and DD).47

Recently, a genetic basis for other forms of “salt-sensitive” hypertension, that resulting from a chimeric mutation of the 11β-hydroxylase/aldosterone synthase gene (glucocorticoid remediable hypertension)48 as well as that resulting from a mutation in the β-subunit of the epithelial sodium channel (Liddle’s syndrome),49 has been described. It is possible that some individuals with salt-sensitive blood pressure may be found to have more subtle genetic abnormalities of any of these forms, which may permit early identification of susceptibility to the blood pressure–raising effects of salt in the future.

Physiological Factors Associated With Salt Sensitivity

Renal Function

Abundant evidence from a variety of studies in humans suggests a renal abnormality or multiple alterations in renal function in salt-sensitive hypertension. Earlier studies have provided indirect evidence for differences in renal function in older subjects, blacks, and individuals with first-degree relatives with hypertension.5051 Whereas these studies were conducted in normotensive subjects, more recent studies conducted in hypertensive men demonstrated racial differences in the response of glomerular filtration rate to dietary sodium loading.52 Even though no significant differences in blood pressure response to the salt load were seen when black and white subjects were compared, the former had a significant increase in glomerular filtration, suggesting hyperfiltration and leading the authors to conclude that renal perfusion pressure was a greater determinant of glomerular filtration in black hypertensive patients than in their white counterparts.52 It should be emphasized that these indirect reports did not describe differences in blood pressure response to salt in the subjects studied.505152 Another group studied hypertensive individuals and categorized their blood pressure responses as well as hemodynamic alterations to low (20 mmol/d) and high (200 mmol/d) sodium intake.53 They found that the salt-sensitive subjects were all blacks who demonstrated a decrease in renal blood flow in response to the high salt diet, whereas the salt-resistant group, which included all of the white subjects as well as some blacks, showed an increase in renal blood flow.53 Furthermore, in a study of 22 Italian hypertensive patients observed after 7 days of 250 mmol salt per day and 7 days of 20 mmol/d, urinary albumin excretion was noted to be significantly greater in the 12 subjects defined as salt sensitive.54 There were no observable differences in glomerular filtration rate, renal plasma flow, or filtration fraction between the two groups during the low sodium period. However, during the high salt diet, renal plasma flow decreased and filtration fraction and intraglomerular pressure increased in the salt-sensitive but not in the salt-resistant group. The investigators of both studies interpreted these findings as indicative of a selective increase in glomerular capillary pressure with high salt intake in the salt-sensitive subjects only.5354 Two groups have observed that salt-sensitive subjects differ from their salt-resistant counterparts in their ability to achieve sodium balance when subjected to a low sodium diet.3455 In both studies, which used 7 days or more of dietary sodium restriction (≤20 mmol/d), a significantly longer half-time in urinary sodium excretion was observed in the salt-sensitive subjects. Some investigators have suggested that alterations in glomerular surface area or the actual density of glomeruli may be responsible for salt-sensitive hypertension.5657 In support of this hypothesis, observations in both experimental animals and humans have been cited that provide substantial indirect evidence that salt sensitivity is associated with a reduction in nephron number or glomerular surface area.56

The Renin-Angiotensin-Aldosterone System

Most161929303839 but not all4558 investigators have reported lower levels of plasma renin activity and, often, of plasma aldosterone concentrations in salt-sensitive subjects. It is not clear whether those studies that were unable to identify reduced activity of the renin-angiotensin-aldosterone system used adequate procedures for evaluating the values in relationship to the state of sodium balance. The implications of these observations are twofold. First, since suppression of plasma renin activity may reflect a relative expansion of extracellular fluid volume and/or sodium balance and since salt sensitivity represents an increase in the blood pressure response to sodium and volume depletion (at least in the studies using such an approach), one would predict that the greatest fall in blood pressure would be likely in the most volume-expanded subjects, that is, in those with the lowest renin levels. An alternative explanation is also feasible. Since the renin-angiotensin-aldosterone system protects against sodium and volume depletion and maintains vascular homeostasis during such situations, individuals in whom the system is relatively unresponsive could be expected to have a greater permissive fall in blood pressure in such circumstances. Evidence in support of this hypothesis can be found from our observations when we compared blood pressure responses to a rapid sodium and volume expansion and contraction maneuver with responses in the same individuals after 5 days of a high salt diet and 7 days of a low salt diet.34 In every case, saline infusion and low sodium diet plus furosemide (rapid protocol) were performed first, and the dietary study was conducted at least 3 months later. We found that the response of plasma renin activity to sodium and water depletion induced by the low salt diet and furosemide predicted (correlated with, P<.001) the blood pressure response to the low salt diet in the second study, which was conducted much later.34 In other words, the subjects with the smallest increase in plasma renin activity following sodium and water depletion had the greatest fall in blood pressure after the low sodium diet and vice versa.

A subgroup of hypertensive patients has been described in whom the “normal” alterations in renal blood flow associated with a high dietary sodium intake and a “normal” response of plasma aldosterone to administered angiotensin II are not seen. This subgroup has been defined as non-modulators, and many but not all of the subjects in this subgroup have been characterized as salt sensitive in terms of their blood pressure response to alterations in dietary sodium intake.59 Of 15 non-modulating hypertensive patients studied, 9 had an increase in diastolic pressure after change from a low (20 mmol/d) to a high (200 mmol/d) sodium intake, a proportion similar to the 5 of 10 modulating hypertensive patients who also demonstrated a sodium-related increase in diastolic pressure in that study.59 The aberrant responses of the non-modulators appeared to be reversed when angiotensin-converting enzyme inhibitors were given.59 The investigators describing these individuals were careful to exclude those with suppressed levels of plasma renin activity and thus, to a large degree, older subjects and blacks,60 who have been reported by others to have the highest prevalence of salt sensitivity. These observations have been extended to normotensive subjects, and a recent report from the same group indicates that one non-modulating normotensive individual in whom long-term follow-up was obtained became hypertensive with the passage of time.61 The relationship between the non-modulating trait and salt sensitivity has been repeatedly inferred, but the documentation appears to be inconsistent because not all non-modulators demonstrated a rise in blood pressure with salt loading and some modulators did.59 These findings, if confirmed, would further support a link between the kidney, renin-angiotensin-aldosterone system, and salt sensitivity of blood pressure.

Atrial Natriuretic Factor

Several investigators have examined the role of atrial natriuretic factor (ANF) in salt sensitivity of blood pressure. Since this peptide is responsible for renal handling of sodium and water and is modulated by alterations in volume status, it is a logical candidate for involvement in the response of blood pressure to such changes. One study suggests that salt-sensitive hypertensive men have lower levels of ANF after a high salt intake than subjects whose blood pressure is not salt sensitive.58 In another study, in which the investigators characterized their hypertensive patients as being low-renin hypertensive patients, non-modulators, or modulators, the investigators reported that the non-modulators had a decreased response of ANF to an intravenous saline load.62 The authors interpreted their findings as indicative of an alteration in the distribution of the volume load in the different groups. These same investigators reported observations in a smaller group of 22 hypertensive men in whom the blood pressure response to changes in sodium balance permitted them to classify 8 as salt sensitive and 7 as salt resistant. When ANF was infused, those who were salt sensitive demonstrated an increase in both insulin and glucose levels after cessation of ANF, whereas the salt-resistant subjects did not.63 This link between salt sensitivity and abnormalities of insulin and glucose will be covered in greater detail below.

Another factor responsible for the renal handling of salt and water that has been implicated in salt sensitivity of blood pressure has been the kallikrein-kinin system. It has been reported that salt-sensitive hypertensive patients have lower levels of urinary kallikrein than those who are salt resistant.28 Moreover, these investigators reported an inverse relationship between ANF and kallikrein in salt-sensitive subjects,28 although they also reported that non-modulators had a decreased response of ANF to saline infusion.62 This apparent discrepancy suggests that salt sensitivity and non-modulation, at least as defined by this group, may not be synonymous, although they observed salt sensitivity of blood pressure in the low-renin and non-modulating groups only.62 In another study,64 the same group of investigators observed that 10 salt-sensitive hypertensive patients had a decrease in blood pressure after oral administration of kallikrein that was not seen in salt-resistant subjects despite similar natriuretic responses to kallikrein in the two groups. These investigators also found lower levels of urinary kallikrein and higher levels of ANF in their salt-sensitive hypertensive patients.64 Other investigators have provided additional support for differences in kallikrein activity in salt-sensitive and salt-resistant subjects.6566

The Sympathetic Nervous System

A variety of studies have implicated the sympathetic nervous system in salt sensitivity of blood pressure. Although impressive, not all of the findings of many investigators examining components of this system have provided support for this hypothesis. Campese et al18 were the first to suggest a role of sympathetic activity in salt-sensitive human hypertension when they observed higher levels of plasma norepinephrine in salt-sensitive compared with salt-resistant hypertensive patients. However, these findings have not been confirmed by all investigators; many have reported no differences in plasma or urinary norepinephrine levels between salt-sensitive and salt-resistant groups.16293858 Venous plasma norepinephrine may not adequately reflect systemic or renal sympathetic activity, which are more relevant sites for the influence of this system on blood pressure and sodium metabolism. In addition, measurements of norepinephrine alone may not fully reflect variations in nervous system control of renal sodium handling. A recent study reported direct measurements of muscle sympathetic nerve activity in black and white hypertensive subjects at rest and with handgrip or cold pressor stress.67 Although the investigators did not characterize the salt responsiveness of blood pressure in this study, they were unable to detect differences in muscle sympathetic nerve activity between the groups, which included black hypertensive subjects, who are known to have a greater frequency of salt sensitivity.67

The role of the dopaminergic system in renal sodium handling and a direct influence of the state of sodium balance on this system were demonstrated more than 20 years ago.68 Our group evaluated the relationship between dopamine and the noradrenergic system and alterations in sodium and water balance in normotensive and hypertensive men.69 We measured urinary dihydroxyphenylacetic acid (DOPAC), the major urinary metabolite of dopamine, and norepinephrine after periods of low (10 mmol/d) and high (800 mmol/d) sodium intake. We derived a “natriuretic index” by comparing the excretion of DOPAC with that of norepinephrine. The ratio increased more than twofold with the high sodium diet in normotensive men. We further observed that hypertensive men, and particularly blacks, had lower levels of the natriuretic index than did the normotensive subjects.69 Recent reports from other investigators indicate that nine salt-sensitive hypertensive patients had higher urinary excretion of dihydroxyphenylalanine and reduced dopamine excretion during a high salt diet than seven salt-resistant hypertensive patients.70 These findings suggest that the dopaminergic system and perhaps the noradrenergic system in the kidney may be different in salt-sensitive and salt-resistant hypertensive patients. To date, clear confirmation of a causal relationship based on pharmacological interventions is not available.

Adrenergic Receptors

Despite inconsistent reports of differences in plasma or urinary levels of norepinephrine between salt-sensitive and salt-resistant individuals, another aspect of the biology of the sympathetic nervous system, adrenergic receptor activity, may be important. Feldman et al71 have demonstrated that β-adrenergic receptor activity is responsive to changes in sodium balance and that β-receptor activity decreases in hypertensive patients. Skrabal and colleagues72 have reported alterations in adrenergic receptor activity with changes in sodium intake in normotensive subjects. Specifically, they observed upregulation of α2-receptors and downregulation of β2-receptors during high sodium intake. They then hypothesized that an increase in the ratio between α2- and β2-receptors during a high salt diet could promote vasoconstriction and decreased vasodilation in resistance vessels and increased proximal tubular sodium reabsorption, which would favor a salt-sensitive blood pressure response.72 They tested this hypothesis by measuring blood pressure and adrenoceptor activity in cultured fibroblasts obtained from 20 normotensive men classified on the basis of their blood pressure response to alterations in dietary sodium intake.73 They found that the salt-sensitive subjects had a reduced number of β2-receptors on their cultured fibroblasts, and they observed a correlation between the change in blood pressure with the alteration of sodium intake and the number of β2-receptors.73 These findings contrast with the findings of Mills and colleagues,74 who used isoproterenol-stimulated cAMP production by lymphocytes as an indirect measure of β-receptor activity. Using this technique, the investigators reported that black hypertensive patients had the most sensitive β-receptors as well as the highest receptor density when compared with white hypertensive patients and normotensive subjects of both racial groups.74 They also observed an inverse correlation between plasma levels of epinephrine and β-receptor density. They did not, however, classify the blood pressure responses of their subjects to changes in sodium balance.

Several investigators have studied vascular responsiveness in salt-sensitive and salt-resistant hypertensive patients.7576 Although these studies did not examine receptor behavior, they demonstrated that salt-sensitive hypertensive patients had decreased large vessel compliance75 and increased pressor responses to angiotensin II and norepinephrine.76

Endothelin and Nitric Oxide

Current interest has been directed toward the potential role of locally acting substances such as endothelin and nitric oxide in the blood pressure response to salt. Endothelin is known to have diuretic and natriuretic effects. Plasma and urinary levels of endothelin-1 were measured in 19 normotensive and 17 hypertensive subjects.77 No differences were seen in plasma endothelin levels, but urinary endothelin was three times higher in normotensive than hypertensive individuals. Salt-sensitive subjects had lower urinary endothelin levels than salt-resistant individuals.77 Further investigation of this preliminary finding may yield new information about the role of this system in hypertension generally and in salt-sensitive hypertensive subjects specifically.

Animal studies have suggested a role for the nitric oxide system in salt-sensitive models of hypertension. Since nitric oxide also causes renal vasodilation and natriuresis, a reduction in nitric oxide synthesis could increase the pressor effects of salt administration. This was demonstrated in rats given NG-nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthesis, which produced an increase in blood pressure compared with vehicle administration with the same dietary salt load.78 The role of nitric oxide in renal handling of sodium and the effects of alterations in sodium balance on arterial pressure are exciting areas of exploration in human biology.

Ion Transport

It is important to recognize that sodium alone may not be responsible for salt-sensitive hypertension, as studies in both experimental animals79 and humans8081 have demonstrated that when sodium is given as the chloride salt, the blood pressure response is greater than when the same amount of sodium is administered in nonchloride forms. These observations implicate the chloride ion in the pathogenesis of salt-induced blood pressure change. The practical significance of this finding is not clear, because more than 95% of sodium ingested in the human diet is in the chloride form.

Abnormalities in intracellular ion transport have long been postulated as being involved in human hypertension in general and in salt-sensitive forms in particular. However, many of the early reports of abnormalities in ion transport identified from studies of erythrocyte biology in vitro were confounded by issues of drug treatment; the contribution of obesity, racial, ethnic, or genetic differences; and other factors that were difficult to separate from the hypertensive process. Furthermore, questions about the causal nature of identified abnormalities were also raised by some critics.

In a recent study conducted in 19 hypertensive patients after 2 months of adherence to a low (50 mmol/d) and high (200 mmol/d) sodium intake, the investigators observed an increase in intracellular (erythrocyte) calcium and sodium concentrations and a reduction in magnesium concentration during salt loading, primarily in salt-sensitive subjects.82 Moreover, the investigators reported a correlation between the changes in ion concentration and the blood pressure response to the salt load.82 Sodium-lithium countertransport has also been implicated as an important abnormality in hypertensive patients.83 In an attempt to link the red blood cell transport abnormality to an alteration in renal tubular sodium handling, we studied both erythrocyte sodium-lithium countertransport in vitro and lithium clearance in vivo in normotensive and hypertensive humans. We found that the hypertensive patients had an increased sodium-lithium countertransport, confirming numerous earlier reports. We also found that despite similar baseline values for the fractional excretion of sodium between normotensive and hypertensive individuals, the fractional excretion of lithium was higher in those with elevated blood pressure.83 Moreover, volume expansion caused a greater natriuresis and greater increase in fractional excretion of lithium among the hypertensive patients. These findings suggested to us that hypertensive patients do not have increased proximal tubular sodium reabsorption and that the exaggerated natriuresis often observed in hypertension is the result of increased distal tubular sodium delivery.83 These observations have been confirmed in a group of Italian hypertensive patients.84

Not only have abnormalities of intracellular sodium, calcium, and magnesium concentrations been implicated in salt-sensitive hypertension,8285 but alterations in extracellular pH and bicarbonate have been found even before the development of hypertension in salt-sensitive normotensive subjects.86 These studies showed that a decrease in cumulative bicarbonate excretion occurred when the salt-sensitive subjects were given sodium citrate or ammonium chloride compared with their salt-resistant counterparts.86 More recent studies have further pursued the issue of sodium-hydrogen ion exchange. A correlation has recently been shown between erythrocyte sodium-hydrogen ion exchange and microalbuminuria in essential hypertensive patients.87 This antiport system has been linked to salt sensitivity88 and cytosolic calcium transport89 in one hypothesis. The latter has suggested, very plausibly, that these abnormalities may be reflected by increased contractility of vascular smooth muscle and increased sodium reabsorption by the renal tubule and may be related to insulin resistance in skeletal muscle by related alterations in intracellular calcium concentrations and increased activity of protein kinase C.89

During high sodium intake, increases in lymphocyte calcium concentration have been reported in salt-sensitive but not in salt-resistant hypertensive patients.90 Salt-sensitive patients have been found to have increased ionized and total serum calcium levels and a calciuric response to a high salt diet compared with salt-resistant hypertensive patients.91 The investigators hypothesized that salt loading shifted calcium from the protein-bound to ionized form.91 Resnick92 has reported that salt-sensitive subjects have an increase in cytosolic free calcium and a decrease in free magnesium levels; also, salt sensitivity is dependent on extracellular calcium concentration, whereas salt resistance is influenced by both renin and intracellular calcium concentrations.93 Both 1,25-dihydroxyvitamin D and the newly identified parathyroid hypertensive factor facilitate calcium transport from the extracellular space to the cell, and both are found to be increased in blacks and low-renin hypertensive subjects.9394

The role of these observations in salt sensitivity of blood pressure was further supported by studies of the effect of oral calcium supplementation in salt-sensitive hypertensive patients.9596 In one study, administration of 2.16 g/d supplemental calcium attenuated the rise in blood pressure observed with a high (300 mmol/d) sodium diet.95 During calcium supplementation, increases in urinary sodium excretion and erythrocyte magnesium content were observed.95 In another study, a supplemental amount of calcium carbonate (1.5 g/d) was given for 8 weeks during a normal dietary sodium intake that significantly reduced blood pressure in patients who had been previously demonstrated to be salt sensitive, whereas the same calcium supplement was associated with an increase in blood pressure in salt-resistant individuals.96 The calcium-sensitive subjects had lower renin levels and higher urinary calcium excretion at baseline as well as after supplementation than did the calcium-resistant subjects.96 These observations suggest that the urinary calcium “leak” reported in hypertensive patients is a feature of salt sensitivity.

Potassium has also been shown to play a role in salt sensitivity of blood pressure. Marked dietary sodium loading is known to cause potassium depletion.13 When potassium loss was prevented by potassium supplementation during sodium loading, the salt-induced blood pressure elevation was attenuated.97 Other investigators have shown a “cardioprotective” effect of potassium independent of its effects on blood pressure,9899 which makes this interaction of additional importance in salt-sensitive hypertension.

Insulin

Hypertensive patients have been shown to be insulin resistant, and because insulin can promote renal sodium reabsorption, several investigators have suggested that hyperinsulinemia may be involved in the pathogenesis of salt sensitivity of blood pressure.100 This concept is based primarily on the improvement of both blood pressure and insulin sensitivity in obese adolescents after weight loss.100 Hyperinsulinemia and salt sensitivity of blood pressure were found to be associated in young blacks.27 However, not all investigators have found salt-sensitive individuals to be hyperinsulinemic. Among seven salt-sensitive normotensive subjects, the investigators observed insulin levels that were similar to those of salt-resistant subjects in the face of glucose levels that were 50% higher.101 These findings suggest that even before hypertension has developed, insulin resistance but not hyperinsulinemia is present. Ferri and colleagues63 were only able to demonstrate hyperinsulinemia and insulin resistance in salt-sensitive subjects after infusion of ANF. Other investigators have been unable to document a difference in insulin levels between salt-sensitive and salt-resistant subjects although differences in regional blood flow in response to insulin were observed during a high salt diet.102 At least one study in a small number of hypertensive patients suggests that it is salt-resistant subjects who are insulin resistant, as a correlation was observed between salt sensitivity and glucose disposal rate.103 A study of Japanese hypertensive patients failed to demonstrate a relationship between salt sensitivity and glucose-insulin dynamics.104 In that study, a low salt diet was associated with a deterioration of insulin sensitivity as evaluated by the response of insulin and glucose to a glucose challenge.104

Summary

Abundant evidence from epidemiological and interventional studies has established heterogeneity in the blood pressure responses of humans to alterations in sodium and extracellular fluid balance. Such changes have been demonstrated in both normotensive and hypertensive subjects. Although the manipulations and criteria used for the assessment of salt responsiveness in humans have differed among investigators, there has been general agreement regarding the major observations. The techniques used have been found to be reproducible when repeated in the same subject, and the responses of at least two different protocols have yielded congruent responses when tested in the same subjects. Some consistent demographic factors, such as older age, black race, and perhaps female sex, have been shown to be associated with an increased frequency of salt sensitivity. Evidence has also been found to support the notion that blood pressure response to changes in salt balance may be genetically determined.

Extensive studies have been conducted to identify the physiological abnormality responsible for the heterogeneity of salt responses. Alterations in the renal handling of salt loads have been shown in salt-sensitive subjects as well as several abnormalities of the renin-angiotensin-aldosterone system. Salt-sensitive subjects are reported to have lower levels of renin and aldosterone than their salt-resistant counterparts. It is not clear whether this is a primary event, a response to real or perceived extracellular volume expansion, or a permissive component that allows a greater decrease in blood pressure with sodium and volume depletion. ANF and renal kallikrein have also been implicated by some studies. A role for the sympathetic nervous system or its receptors has also been suggested by some investigators. Abnormalities of ion transport, involving vascular smooth muscle as well as renal tubular cells, have been invoked, perhaps linked not only to sodium transport but to the ion transport of calcium and potassium as well. Other investigators have proposed a role for abnormalities in the response to insulin in salt sensitivity of blood pressure, but this link is not clearly established. Recent studies of endothelin and nitric oxide indicate that they are also plausible candidates for involvement in salt-sensitive vascular responses.

At present, we recognize that a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt balance. Future studies should elucidate the genetic basis for this phenomenon and identify factors, inherent or acquired, contributing to it; the compensatory mechanisms that typically guard against the pressor actions of salt loads and that may be impaired in some individuals; and more effective ways of treating this response. Finally, such information should provide the basis for an approach to the primary prevention of salt-sensitive forms of hypertension in humans.